1. Field of the Invention
This invention relates to a fluidic medical diagnostic device for measuring the concentration of an analyte in or a property of a biological fluid.
2. Description of the Related Art
A variety of medical diagnostic procedures involve tests on biological fluids, such as blood, urine, or saliva, and are based on a change in a physical characteristic of such a fluid or an element of the fluid, such as blood serum. The characteristic can be an electrical, magnetic, fluidic, or optical property. When an optical property is monitored, these procedures may make use of a transparent or translucent device to contain the biological fluid and a reagent. A change in light absorption of the fluid can be related to an analyte concentration in, or property of, the fluid. Typically, a light source is located adjacent to one surface of the device and a detector is adjacent to the opposite surface. The detector measures light transmitted through a fluid sample. Alternatively, the light source and detector can be on the same side of the device, in which case the detector measures light scattered and/or reflected by the sample. Finally, a reflector may be located at or adjacent to the opposite surface. A device of this latter type, in which light is first transmitted through the sample area, then reflected through a second time, is called a xe2x80x9ctransflectancexe2x80x9d device. References to xe2x80x9clightxe2x80x9d throughout this specification and the appended claims should be understood to include the infrared and ultraviolet spectra, as well as the visible. References to xe2x80x9cabsorptionxe2x80x9d are meant to refer to the reduction in intensity as a light beam passes through a medium; thus, it encompasses both xe2x80x9ctruexe2x80x9d absorption and scattering.
An example of a transparent test device is described in Wells et al. WO94/02850, published on Feb. 3, 1994. Their device comprises a sealed housing, which is transparent or translucent, impervious, and rigid or semi-rigid. An assay material is contained within the housing, together with one or more assay reagents at predetermined sites. The housing is opened and the sample introduced just before conducting the assay. The combination of assay reagents and analyte in the sample results in a change in optical properties, such as color, of selected reagents at the end of the assay. The results can be read visually or with an optical instrument.
U.S. Pat. No. 3,620,676, issued on Nov. 16, 1971 to Davis, discloses a calorimetric indicator for liquids. The indicator includes a xe2x80x9chalf-bulb cavityxe2x80x9d, which is compressible. The bulb is compressed and released to form a suction that draws fluid from a source, through a half-tubular cavity that has an indicator imprinted on its wall. The only controls on fluid flow into the indicator are how much the bulb is compressed and how long the indicator inlet is immersed in the source, while the bulb is released.
U.S. Pat. No. 3,640,267, issued on Feb. 8, 1972 to Hurtig et al., discloses a container for collecting samples of body fluid that includes a chamber that has resilient, collapsible walls. The walls are squeezed before the container inlet is placed into the fluid being collected. When released, the walls are restored to their uncollapsed condition, drawing fluid into and through the inlet. As with the Davis device, discussed above, control of fluid flow into the indicator is very limited.
U.S. Pat. No. 4,088,448, issued on May 9, 1978 to Lilja et al., discloses a cuvette, which permits optical analysis of a sample mixed with a reagent. The reagent is coated on the walls of a cavity, which is then filled with a liquid sample. The sample mixes with the reagent to cause an optically-detectable change.
A number of patents, discussed below, disclose devices for diluting and/or analyzing biological fluid samples. These devices include valve-like designs to control the flow of the sample.
U.S. Pat. No. 4,426,451, issued on Jan. 17, 1984 to Columbus, discloses a multi-zone fluidic device that has pressure-actuatable means for controlling the flow of fluid between the zones. His device makes use of pressure balances on a liquid meniscus at the interface between a first zone and a second zone that has a different cross section. When both the first and second zones are at atmospheric pressure, surface tension creates a back pressure that stops the liquid meniscus from proceeding from the first zone to the second. The configuration of this interface or xe2x80x9cstop junctionxe2x80x9d is such that the liquid flows into the second zone only upon application of an externally generated pressure to the liquid in the first zone that is sufficient to push the meniscus into the second zone.
U.S. Pat. No. 4,868,129, issued on Sep. 19, 1989 to Gibbons et al., discloses that the back pressure in a stop junction can be overcome by hydrostatic pressure on the liquid in the first zone, for example by having a column of fluid in the first zone.
U.S. Pat. No. 5,230,866, issued on Jul. 27, 1993 to Shartle et al., discloses a fluidic device with multiple stop junctions in which the surface tension-induced back pressure at the stop junction is augmented; for example, by trapping and compressing gas in the second zone. The compressed gas can then be vented before applying additional hydrostatic pressure to the first zone to cause fluid to flow into the second zone. By varying the back pressure of multiple stop junctions in parallel, xe2x80x9crupture junctionsxe2x80x9d can be formed, having lower maximum back pressure.
U.S. Pat. No. 5,472,603, issued on Dec. 5, 1995 to Schembri (see also U.S. Pat. No. 5,627,041), discloses using centrifugal force to overcome the back pressure in a stop junction. When flow stops, the first zone is at atmospheric pressure plus a centrifugally generated pressure that is less than the pressure required to overcome the back pressure. The second zone is at atmospheric pressure. To resume flow, additional centrifugal pressure is applied to the first zone, overcoming the meniscus back pressure. The second zone remains at atmospheric pressure.
European Patent Application EP 0 803 288, of Naka et al., published on Oct. 29, 1997, discloses a device and method for analyzing a sample that includes drawing the sample into the device by suction, then reacting the sample with a reagent in an analytical section. Analysis is done by optical or electrochemical means. In alternate embodiments, there are multiple analytical sections and/or a bypass channel. The flow among these sections is balanced without using stop junctions.
U.S. Pat. No. 5,700,695, issued on Dec. 23, 1997 to Yassinzadeh et al., discloses an apparatus for collecting and manipulating a biological fluid that uses a xe2x80x9cthermal pressure chamberxe2x80x9d to provide the driving force for moving the sample through the apparatus.
U.S. Pat. No. 5,736,404, issued on Apr. 7, 1998, to Yassinzadeh et al., discloses a method for determining the coagulation time of a blood sample that involves causing an end of the sample to oscillate within a passageway. The oscillating motion is caused by alternately increasing and decreasing the pressure on the sample.
The present invention provides a fluidic diagnostic device for measuring an analyte concentration or property of a biological fluid. The device comprises
a first layer and second layer at least one of which has a resilient region over at least part of its area, separated by an intermediate layer, in which cutouts in the intermediate layer form, with the first and second layers,
a) a sample port for introducing a sample of the biological fluid into the device;
b) a first measurement area, in which a physical parameter of the sample is measured and related to the analyte concentration or property of the fluid;
c) a first channel, having a first end and a second end, to provide a fluidic path from the sample port at the first end through the first measurement area;
d) a first bladder at the second end of the first channel, comprising at least a part of the resilient region in at least the first or second layer and having a volume that is at least about equal to the combined volume of the first measurement area and first channel; and
e) a first stop junction in the first channel between the first measurement area and first bladder that comprises a co-aligned through hole in at least the first or second layer, the through hole being overlaid with a third layer.
In another embodiment, the device comprises
a first layer, which has a resilient region over at least a part of its area, and a second layer, separated by an intermediate layer, in which recesses in a first surface of the intermediate layer form, with the first layer,
a) a sample port for introducing a sample of the biological fluid into the device;
b) a measurement area, in which the sample undergoes a change in a physical parameter that is measured and related to the analyte concentration or property of the fluid;
c) a channel, having a first end and a second end, to provide a fluidic path from the sample port at the first end through the measurement area; and
d) a bladder, at the second end of the channel, comprising at least a part of the resilient region in the first layer and having a volume that is at least about equal to the combined volume of the measurement area and channel; and
a stop junction in the channel between the measurement area and bladder that comprises two passages substantially normal to the first surface of the intermediate layer, each passage having a first end in fluid communication with the channel and a second end in fluid communication with a recess in a second surface of the intermediate layer, which recess provides fluid communication between the second ends of the passages.
The device is particularly well adapted for measuring prothrombin time (PT time), with the biological fluid being whole blood and the measurement area having a composition that catalyzes the blood clotting cascade.